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Richard Rozmahel

Bio: Richard Rozmahel is an academic researcher from University of Western Ontario. The author has contributed to research in topics: Cystic fibrosis transmembrane conductance regulator & Presenilin. The author has an hindex of 25, co-authored 41 publications receiving 12346 citations. Previous affiliations of Richard Rozmahel include Université de Sherbrooke & Lawson Health Research Institute.

Papers
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Journal ArticleDOI
08 Sep 1989-Science
TL;DR: A deletion of three base pairs that results in the omission of a phenylalanine residue at the center of the first predicted nucleotide-binding domain was detected in CF patients.
Abstract: Overlapping complementary DNA clones were isolated from epithelial cell libraries with a genomic DNA segment containing a portion of the putative cystic fibrosis (CF) locus, which is on chromosome 7 Transcripts, approximately 6500 nucleotides in size, were detectable in the tissues affected in patients with CF The predicted protein consists of two similar motifs, each with (i) a domain having properties consistent with membrane association and (ii) a domain believed to be involved in ATP (adenosine triphosphate) binding A deletion of three base pairs that results in the omission of a phenylalanine residue at the center of the first predicted nucleotide-binding domain was detected in CF patients

6,731 citations

Journal ArticleDOI
08 Sep 1989-Science
TL;DR: Several transcribed sequences and conserved segments were identified in this cloned region and one corresponds to the cystic fibrosis gene and spans approximately 250,000 base pairs of genomic DNA.
Abstract: An understanding of the basic defect in the inherited disorder cystic fibrosis requires cloning of the cystic fibrosis gene and definition of its protein product. In the absence of direct functional information, chromosomal map position is a guide for locating the gene. Chromosome walking and jumping and complementary DNA hybridization were used to isolate DNA sequences, encompassing more than 500,000 base pairs, from the cystic fibrosis region on the long arm of human chromosome 7. Several transcribed sequences and conserved segments were identified in this cloned region. One of these corresponds to the cystic fibrosis gene and spans approximately 250,000 base pairs of genomic DNA.

3,050 citations

Journal ArticleDOI
01 May 1991-Genomics
TL;DR: Although an internal amino acid sequence homology could be detected between the two halves of the predicted polypeptide, the lack of alignment of the nucleotide sequence as well as the different positions of the exon/intron boundaries does not seem to support the hypothesis of a recent gene duplication event.

542 citations

Journal ArticleDOI
TL;DR: Electrophysiological studies on mice with prolonged survival show that the partial rectification of Cl− and Na+ ion transport abnormalities can be explained in part by up-regulation of a calcium-activated Cl− conductance.
Abstract: Mice that have been made deficient for the cystic fibrosis transmembrane conductance regulator (Cftr) usually die of intestinal obstruction. We have created Cftr-deficient mice and demonstrate prolonged survival among backcross and intercross progeny with different inbred strains, suggesting that modulation of disease severity is genetically determined. A genome scan showed that the major modifier locus maps near the centromere of mouse chromosome 7. Electrophysiological studies on mice with prolonged survival show that the partial rectification of Cl- and Na+ ion transport abnormalities can be explained in part by up-regulation of a calcium-activated Cl- conductance. Identification of modifier genes in our Cftr(m1HSC)/Cftr(m1HSC) mice should provide important insight into the heterogeneous disease presentation observed among CF patients.

394 citations

Journal ArticleDOI
TL;DR: It is reported here that presenilin mutations associated with familial Alzheimer disease (but not the non–pathogenic Glu318Gly polymorphism) alter the intracellular trafficking of β-catenin after activation of the Wnt/β- catenin signal transduction pathway.
Abstract: The presenilin proteins are components of high-molecular-weight protein complexes in the endoplasmic reticulum and Golgi apparatus that also contain beta-catenin We report here that presenilin mutations associated with familial Alzheimer disease (but not the non-pathogenic Glu318Gly polymorphism) alter the intracellular trafficking of beta-catenin after activation of the Wnt/beta-catenin signal transduction pathway As with their effect on betaAPP processing, the effect of PS1 mutations on trafficking of beta-catenin arises from a dominant 'gain of aberrant function' activity These results indicate that mistrafficking of selected presenilin ligands is a candidate mechanism for the genesis of Alzheimer disease associated with presenilin mutations, and that dysfunction in the presenilin-beta-catenin protein complexes is central to this process

226 citations


Cited by
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Journal ArticleDOI
08 Sep 1989-Science
TL;DR: A deletion of three base pairs that results in the omission of a phenylalanine residue at the center of the first predicted nucleotide-binding domain was detected in CF patients.
Abstract: Overlapping complementary DNA clones were isolated from epithelial cell libraries with a genomic DNA segment containing a portion of the putative cystic fibrosis (CF) locus, which is on chromosome 7 Transcripts, approximately 6500 nucleotides in size, were detectable in the tissues affected in patients with CF The predicted protein consists of two similar motifs, each with (i) a domain having properties consistent with membrane association and (ii) a domain believed to be involved in ATP (adenosine triphosphate) binding A deletion of three base pairs that results in the omission of a phenylalanine residue at the center of the first predicted nucleotide-binding domain was detected in CF patients

6,731 citations

Journal ArticleDOI
TL;DR: Bulk segregant analysis has several advantages over the use of near-isogenic lines to identify markers in specific regions of the genome and will have widespread application both in those species where selfing is possible and in those that are obligatorily outbreeding.
Abstract: We developed bulked segregant analysis as a method for rapidly identifying markers linked to any specific gene or genomic region. Two bulked DNA samples are generated from a segregating population from a single cross. Each pool, or bulk, contains individuals that are identical for a particular trait or genomic region but arbitrary at all unlinked regions. The two bulks are therefore genetically dissimilar in the selected region but seemingly heterozygous at all other regions. The two bulks can be made for any genomic region and from any segregating population. The bulks are screened for differences using restriction fragment length polymorphism probes or random amplified polymorphic DNA primers. We have used bulked segregant analysis to identify three random amplified polymorphic DNA markers in lettuce linked to a gene for resistance to downy mildew. We showed that markers can be reliably identified in a 25-centimorgan window on either side of the targeted locus. Bulked segregant analysis has several advantages over the use of near-isogenic lines to identify markers in specific regions of the genome. Genetic walking will be possible by multiple rounds of bulked segregation analysis; each new pair of bulks will differ at a locus identified in the previous round of analysis. This approach will have widespread application both in those species where selfing is possible and in those that are obligatorily outbreeding.

4,492 citations

Journal ArticleDOI
TL;DR: This chapter discusses thebuilding blocks of the Transmembrane Complex, and some of the properties of these blocks have changed since the publication of the original manuscript in 1993.
Abstract: INTRODUCTION .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 DOMAIN ORGANIZATION: The Typical ABC Transporter . . . . . . . . . . . . . . . . . 73 THE TRANSMEMBRANE DOMAINS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 The "Two-Times-Six" Helix Paradigm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Sequence Similarities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 THE ATP-BINDING DOMAINS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 PERIPLASMIC-BINDING PROTEINS ... . 84 SUBSTRATE SPECIFICITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 THE ROLE OF ATP : Coupling Energy to Transport . . . . . . . . . . . . . . . . . . . " . . . . . 88 COVALENT MODIFICATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 CELLULAR FUNCTIONS OF ABC TRANSPORTERS . . . . . . . . . . . . . . . . . . . . . . . 9 1 Nutrient Uptake . . . . . . . . . . . . ....... . 9 1 Protein Export ....... . .... . . . . . . . . . . . . ... . ......... . ...... . ... . .. 93 Intracellular Membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 Regulation of ABC Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Regulation by ABC Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Drug and Antibiotic Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Channel Functions: CFTR and P-glycoprotein . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 MECHANISMS OF SOLUTE TRANSLOCATION . . . . . . . . . . . . . . . . . . . . . . . . . . 98 Structure of the Transmembrane Complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 Channels and Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 0 I Energy Coupling andlor Gating . 102 CONCLUDING REMARKS . 103

3,937 citations

Journal ArticleDOI
08 Sep 1989-Science
TL;DR: Extended haplotype data based on DNA markers closely linked to the putative disease gene locus suggest that the remainder of the cystic fibrosis mutant gene pool consists of multiple, different mutations.
Abstract: Approximately 70 percent of the mutations in cystic fibrosis patients correspond to a specific deletion of three base pairs, which results in the loss of a phenylalanine residue at amino acid position 508 of the putative product of the cystic fibrosis gene. Extended haplotype data based on DNA markers closely linked to the putative disease gene locus suggest that the remainder of the cystic fibrosis mutant gene pool consists of multiple, different mutations. A small set of these latter mutant alleles (about 8 percent) may confer residual pancreatic exocrine function in a subgroup of patients who are pancreatic sufficient. The ability to detect mutations in the cystic fibrosis gene at the DNA level has important implications for genetic diagnosis.

3,816 citations

Journal ArticleDOI
TL;DR: A number of 5-HT receptor ligands are currently utilised, or are in clinical development, to reduce the symptoms of CNS dysfunction and the functional responses attributed to each receptor in the brain are reviewed.

3,074 citations